The long range goal of this research is to define the role(s) of the TNF gene family in reproduction. New experimental approaches have been developed for the purpose of evaluating the functions of trophoblast cell TNFa that include use of knockout (KO) mice carrying deletions of the TNFa/LTa and TNF receptor (TNF-R) genes, and generation of mouse trophoblastic cell lines from these as well as normal mice. Preliminary experiments show that: 1) the TNF signaling system is critical to normal development of placental compartments, 2) TNF/TNF-R signaling is involved in gender-specific pathways that affect normal development, 3) trophoblastic cell lines derived from mouse placentas express the TNFa gene and, 4) under some conditions, trophoblastic cell lines are growth-inhibited by exogenous TNFa. Additional studies demonstrate that two other biologically-potent members of the TNF superfamily, FasL and Lt-beta, are expressed in the uteri and placentae of pregnant mice, and preliminary data strongly suggest that FasL has an important role in restricting maternal-fetal migration of activated hematopoietic cells.